The trans {4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-il]-ethyl}-cyclohexylamine dihydrochloride monohydrate according to the invention is a key intermediate for the preparation of a number of compounds acting on D3/D2 receptor. Similar compounds were described in the Hungarian Patent Specifications No. P0103988 and P0302451, and in Bioorg. Med. Chem. Lett. EN; 7; 18; 1997 2403-2408.
The Hungarian Patent Specification No. P0103988 discloses a reaction route for the preparation of trans {4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-il]-ethyl}-cyclohexylamine dihydrochloride. According to the preparation process described in Example 1, 2,3-dichlorophenyl-piperazine and trans 2-{1-[4-(N-terc-butoxycarbonyl)-amino]-cyclohexyl}-acetaldehyde are dissolved and coupled in dichloromethane in the presence of sodium triacetoxy borohydride to give trans N-{4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-il]-ethyl}-cyclohexyl}-carbamic acid tertiary butylester. Then the protective group is removed in ethyl acetate by hydrochloride acid according to a process described in Example 2. The yield data for trans N-{4-{2-[4-2,3-dichlorophenyl)-piperazine-1-il]-ethyl}-cyclohexyl}-carbamic acid tertiary butylester or for trans N-{4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-il]-ethyl}-cyclohexyl}-amine dihydrochloride are not described either.
The drawback of the above procedure is that when preparing trans 2-{1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl}-acetaldehyde from the corresponding trans 2-{1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl}-acetic acid ester the reaction can be carried out at a temperature below 70° C. and with only 55% yield (Stemp et al. J. Med. Chem. 2000. Vol. 43, No. 9, p. 7878-7885). However, use of the above operating temperature and the very hazardous diisobutyl aluminium hydride mean technological problems in industrial scale therefore the reaction can be carried out only in extra equipments and at extreme conditions.
The procedure disclosed in the above mentioned Bioorg. Med. Chem. Lett. EN; 7; 18; 1997 2403-2408 literature consists of eight reaction steps and the compounds are mentioned only in general without any characterizing features. The eight steps procedure seems to be complicated, expensive and hazardous particularly performing in industrial scale.
Our aim was to provide a safe and in industrial scale easy-to-manage process for the preparation of trans N-{4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-il]-ethyl}-cyclohexylamine key intermediate by which it can be prepared in good yield via simple reaction steps without using extreme reaction conditions and extra equipments.